Abstract 1808: Duffy Antigen Receptor for Chemokines (Darc) Polymorphism Regulates Circulating Concentrations of Monocyte Chemoattractant Protein-1 and Other Circulating Inflammatory Mediators
Background: Monocyte chemoattractant protein (MCP)-1 is a cytokine central to the inflammatory process. The genetics of MCP-1 are little understood.
Methods and Results: To identify the genetic basis of vascular monocyte chemoattractant protein-1 (MCP-1) concentrations, we conducted genome-wide association analyses for for serum and plasma MCP-1 in three independent cohorts (Atherosclerosis Risk in Communities [ARIC], n=818, Framingham Heart Study [FHS], n=7,136, and MONICA/KORA, n=1,644). The strongest association was for serum MCP-1 with a nonsynonymous polymorphism in DARC, the gene for the Duffy Antigen Receptor for Chemokines (Darc), a known vascular reservoir of proinflammatory cytokines (minor allele frequency 45.6%; p<1.0×10−323). This association was supported by family-based genetic linkage at a locus encompassing the DARC gene in the Framingham Heart Study (genome-wide p=8.0*10−13). The SNP accounted for approximately 20% of the variability in serum MCP-1 concentrations, and also was associated with serum levels of interleukin-8 and RANTES. While exploring a lack of association between this polymorphism and EDTA plasma MCP-1 concentrations (p=0.82), we determined that both clotting and exogenous heparan sulphate (unfractionated heparin) released substantial amounts of MCP-1 from Darc. Quantitative immuno-flow cytometry failed to identify meaningful Gly42Asp-associated differences in Darc expression, suggesting a functional change is responsible for the differential cytokine binding.
Conclusions: We conclude that the identified SNP is a major regulator of erythrocyte Darc-mediated cytokine-binding, and thereby the vascular concentrations of several proin-flammatory cytokines. We have also identified for the first time two mechanisms for the release of reservoir chemokines with possible clinical implications in (athero)thrombosis, chronic inflammatory diseases and cancer.